Shock Syndromes II
Dabigatran reversal: Idarucizumab is FDA approved for dabigatran reversal.
Idarucizumab is a monoclonal antibody that binds both bound and unbound dabigatran. It has
a binding affinity to dabigatran that is greater than 350 times that of dabigatran for thrombin.
ii.
In the RE-VERSE AD trial, in the full analysis of 503 patients with life-threatening hemorrhage
or need for urgent procedure, all who received idarucizumab 5 g intravenously had maximum
dilute TT reversal by 4 hours after idarucizumab administration. Given that dabigatran has a
volume of distribution of greater than 50 L, about 23% of patients developed redistribution of
unbound dabigatran and associated coagulopathy at 12–24 hours. The efficacy of repeat doses
in this setting has not been established. The package insert recommends that if there is clinically
relevant bleeding (or need for a second emergency surgery/urgent procedure) in combination
with elevated coagulation parameters (e.g., aPTT, ecarin clotting time), an additional 5-g dose
of idarucizumab may be considered. Therefore, an aPTT should be obtained to rule out the
presence of dabigatran before a repeat dose is given.
iii.
The thrombotic event rate at 90 days was 6.8%. All thrombotic events that occurred within 72
hours were in patients for whom anticoagulation was not reinitiated (also because of half-life
of 45 minutes).
iv.
Given the availability of idarucizumab, adjunctive reversal options such as dialysis should
only be considered if there are concurrent indications on the basis of renal function or if
idarucizumab is ineffective.
Factor Xa inhibitors: Andexanet alfa is FDA approved for rivaroxaban and apixaban reversal in
life-threatening hemorrhage.
Andexanet alfa is a modified factor Xa decoy protein such that it directly binds to the factor Xa
inhibitors in a 1:1 ratio to inactivate their anticoagulant response.
| (a) | Andexanet alfa structural modifications render it incapable of having prothrombotic or |
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antithrombotic effects.
| (b) | Mutation of the active serine site ensures that andexanet lacks the catalytic activity needed |
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to convert prothrombin to thrombin.
| (c) | Deletion of the GLA fragment makes andexanet unable to bind to phospholipids and |
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interact with factor V and calcium to form a prothrombinase complex.
ii.
Andexanet alfa reverses the effects of both direct (DOAC) and indirect (low-molecular-weight
heparin) factor Xa inhibitors.
iii.
The ANNEXA-4 trial evaluated the effects of andexanet alfa in patients with acute major
bleeding and recent ingestion of factor Xa inhibitors, predominantly apixaban and rivaroxaban.
| (a) | After an initial bolus of andexanet, there was a 90%–92% reduction in the anti-factor Xa |
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(anti-Xa) activity from baseline. This was sustained through the 2-hour infusion of the
study drug, allowing for a hemostatic plug to form.
| (b) | Of note, only 72% of patients met the predefined threshold for anticoagulation activity |
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(baseline anti-Xa concentrations of 75 ng/mL or greater for DOACs or 0.25 IU/mL or
greater for enoxaparin) to be included in this efficacy analysis.
| (c) | An important limitation of this study was the exclusion of patients expected to require |
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surgery within 12 hours, a population commonly encountered when treating bleeding
patients.
iv.
Andexanet alfa has a short half-life (1 hour); thus, redistribution and associated anticoagulant
activity are also common after discontinuing andexanet.
| (a) | In theory, this 2-hour time interval allows for a hemostatic plug to form and bleeding |
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to stop.
| (b) | In the ANNEXA-4 trial, anti-Xa activity rebounded. Two hours after discontinuing the |
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infusion, anti-Xa activity decreased only 32%–42% relative to baseline.
| (c) | However, at 12 hours, 82% of patients met the co-primary end point of good or excellent |
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clinical hemostasis. This brings into question the clinical significance of the rebound
effect. Further research is needed to determine the importance of this rebound effect in
patients with ongoing bleeding, patients with critical site bleeds, or surgical populations.